title: The FGFR D3 domain determines receptor selectivity for fibroblast growth factor 21.
abstract: FGF21 is a member of a unique subfamily of fibroblast growth factors that function as endocrine hormones and regulate a variety of metabolic activities. Unlike paracrine FGFs, FGF21 does not bind heparin and requires βKlotho as a co-receptor to activate FGFR signaling. In the presence of βKlotho, FGF21 is able to activate FGFRs 1c, 2c and 3c but not FGFR4. Chimeric FGFR1c/FGFR4 receptors were constructed to identify domains that confer this specificity and to understand regions important for FGF21-induced receptor activation. With these chimeras, we showed that domain 3 of the FGFR1c extracellular domain plays a critical role in specificity determination and receptor activation by FGF21. Furthermore, we were able to narrow down the sequences important for this function to a six amino acid region within domain 3 of FGFR1c. It is interesting to note that this region falls into the βC'-βE loop, which has been shown to be important for receptor specificity determination in paracrine FGFs, suggesting a common principle in both endocrine and paracrine FGF receptor interaction and activation.
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Jamila
authors.initials: J
authors.lastname: Gupte
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Xinle
authors.initials: X
authors.lastname: Wu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Weiszmann
authors.forename: Randy
authors.initials: R
authors.lastname: Hecht
authors.forename: Bryan
authors.initials: B
authors.lastname: Lemon
authors.forename: Richard
authors.initials: R
authors.lastname: Lindberg
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C496348:FGFR1 protein, human; C496371:FGFR4 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051499:Receptor, Fibroblast Growth Factor, Type 4